Colchicine treatment impairs skeletal muscle mitochondrial function and insulin sensitivity in an age‐specific manner

Abstract

The aim of the study was to investigate the impact of autophagy inhibition on skeletal muscle mitochondrial function and glucose homeostasis in young and aged mice. The transcriptional co‐activator PGC‐1α regulates muscle oxidative phenotype which has been shown to be linked with basal autophagic capacity. Therefore, young and aged inducible muscle‐specific PGC‐1α knockout (iMKO) mice and littermate lox/lox controls were used in three separate experiments performed after either saline or colchicine injections on two consecutive days: (1) Euthanization in the basal state obtaining skeletal muscle for mitochondrial respirometry, (2) whole body glucose tolerance test, and (3) in vivo insulin‐stimulated 2‐deoxyglucose (2‐DG) uptake into skeletal muscle. Muscle PGC‐1α was not required for maintaining basal autophagy flux, regardless of age. Colchicine‐induced inhibition of autophagy was associated with impairments of skeletal muscle mitochondrial function, including reduced ADP sensitivity and altered mitochondrial redox balance in both young and aged mice. Colchicine treatment reduced the glucose tolerance in aged, but not young mice, and similarly in iMKO and lox/lox mice. Colchicine reduced insulin‐stimulated 2‐DG uptake in soleus muscle in aged mice, independently of PGC‐1α, and without affecting insulin‐regulated phosphorylation of proximal or distal mediators of insulin signaling. In conclusion, the results indicate that autophagy regulates the mitochondrial ADP sensitivity and redox balance as well as whole body glucose tolerance and skeletal muscle insulin sensitivity in aged mice, with no additional effects of inducible PGC‐1α deletion.

The CARM1 transcriptome and arginine methylproteome mediate skeletal muscle integrative biology

“…The technique used to prepare the EDL and SOL muscles has previously been described [ 59 , 60 ]. Mice were euthanized by cervical dislocation and muscles were quickly removed.…”

Wheel running improves fasting‐induced AMPK signaling in skeletal muscle from tumor‐bearing mice

“…While we did sacrifice ad libitum mice at the end of the dark cycle to utilize the fed condition, it is possible that the circadian rhythms can play a role in the intracellular signaling and should be considered. Furthermore, it is interesting to hypothesize that the cancer environment disrupts the feeding and fasting regulation of autophagy which can be rescued by physical activity; however future studies are needed in order to clarify if and where in the autophagy process these disrupts might be occurring (Buch et al, 2020; Yoshii & Mizushima, 2017). We build on these findings by reporting that the fasting induction autophagy‐related signaling in MIN mice requires AMPK and works through ULK‐1 phosphorylation.…”

Impaired muscle stem cell function and abnormal myogenesis in acquired myopathies

“…Combination of colchicine and statins simultaneously activates autophagy signaling and inhibits the degradation of the newly formed autophagosome, leading to myotoxicity [ 204 ]. Administration of colchicine in young and old mice was shown to impair autophagy resulting in dysfunctions in skeletal muscle mitochondria [ 205 ]. In vitro , the addition of colchicine blocked cell division in myoblasts and led to myotube fragmentation [ 206 ].…”